PROJECT ABSTRACT Chronic methamphetamine (meth) intake has been shown to induce a neuroinflammatory state leading to significant changes in brain functioning, including behavioral changes. These changes can persist for years after drug use is discontinued and likely contribute to the risk of relapse. Unfortunately, there is no approved medication to treat meth use disorder. Accordingly, this project will focus on the anti-inflammatory drug ibudilast (AV-411 or MN-166), a phosphodiesterase inhibitor that modulates the activity of glial cells by suppressing the production of pro-inflammatory cytokines. Ibudilast has recently been fast-tracked by the U.S. Food and Drug Administration to treat progressive multiple sclerosis and is used as an anti-inflammatory in Japan. Recent preclinical research has shown that ibudilast can attenuate meth-seeking behavior in male rats. This project will expand prior work to examine the anti-inflammatory impact of ibudilast on female rats and the role of phosphatidylethanolamine-binding protein 1 (PEBP1) as a novel pathogenic marker for meth seeking. Considerations of biological sex as a differentiating condition for methamphetamine addiction and relapse is driven by recent research showing significant sex differences in methamphetamine-related addiction trajectories among humans. Using an array of complementary behavioral, molecular, and biochemical approaches in a ?gold standard? preclinical model of self-administration, this project will index a role for synaptic PEBP1 as a potential pathogenic marker for meth seeking (Aim 1) and identify changes in neurochemical correlates by ibudilast as biological variables between the sexes (Aim 2). The expected outcomes will elucidate the effectiveness of ibudilast in attenuating inflammation differences between the sexes when administered during the extinction phase. While this project will serve as a springboard for a competitive R01 application by the Project Leader, it will also contribute to the overarching goal of the proposed Rural Drug Addiction Research Center (RDAR)?to understand and develop appropriate interventions for rural drug use and its related harms. The broad, long-term objective of this line of research is to test the efficacy of ibudilast as a repurposed drug to treat synaptic targets of meth in human subjects, which will be made possible through RDAR?s proposed recruitment and retention of a cohort of rural drug users. This project will be conducted by a team of experienced investigators with complementary research expertise and builds on a solid intellectual and methodological foundation resulting from the team?s previous studies. The project also advances Goal One of the National Institute of Drug Abuse?s 2016-2020 Strategic Plan?to investigate the basic science of brain function as it relates to drug use, including component cells and synaptic connections.